Intrinsic and Extrinsic Molecular Determinants Or Modulators For

Polish Journal of Veterinary Sciences Vol. 21, No. 1 (2018), 217–227

DOI 10.24425/119040 Review Intrinsic and extrinsic molecular determinants or modulators for epigenetic remodeling and reprogramming of somatic cell-derived genome in mammalian nuclear-transferred oocytes and resultant embryos

M. Samiec, M. Skrzyszowska

National Research Institute of Animal Production, Department of Reproductive Biotechnology and Cryoconservation, Krakowska 1, 32-083 Balice n. Kraków, Poland

Abstract

The efficiency of somatic cell cloning in mammals remains disappointingly low. Incomplete and aberrant reprogramming of epigenetic memory of somatic cell nuclei in preimplantation nuclear-transferred (NT) embryos is one of the most important factors that limit the cloning effectiveness. The extent of epigenetic genome-wide alterations, involving histone or DNA methylation and histone deacetylation, that are mediated by histone-lysine methyltransferases (HMTs) or DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be modulated/reversed via exogenous inhibitors of these enzymes throughout in vitro culture of nuclear donor cells, nuclear recipient oocytes and/or cloned embryos. The use of the artificial modifiers of epigenomically-conditioned gene expression leads to inhibition of both chromatin condensation and transcriptional silencing the genomic DNA of somatic cells that provide a source of nuclear donors for reconstruction of enucleated oocytes and generation of cloned embryos. The onset of chromatin decondensation and gene transcriptional activity is evoked both through specific/selective inactivating HMTs by BIX-01294 and through non-specific/non-selective blocking the activity of either DNMTs by 5-aza-2’-deoxycytidine, zebularine, S-adenosylhomocysteine or HDACs by trichostatin A, valproic acid, scriptaid, oxamflatin, sodium butyrate, m-carboxycinnamic acid bishydroxamide, panobinostat, abexinostat, quisinostat, dacinostat, belinostat and psammaplin A. Epigenomic modulation of nuclear donor cells, nuclear recipient cells and/or cloned embryos may facilitate and accelerate the reprogrammability for gene expression of donor cell nuclei that have been transplanted into a host ooplasm and subsequently underwent dedifferentiating and re-establishing the epigenetically dependent status of their transcriptional activity during pre- and postimplantation development of NT embryos. Never- theless, a comprehensive additional work is necessary to determine whether failures in the early-stage reprogramming of somatic cell-inherited genome are magnified downstream in development of cloned conceptuses and neonates.

Key words: somatic cell nucleus, reconstructed oocyte, epigenomic maturity, nuclear-transferred embryo, somatic cell-inherited chromatin remodeling, donor nuclear reprogramming, epigenetic modulator/modifier

Correspondence to: M. Samiec, e-mail: [email protected] 218 M. Samiec, M. Skrzyszowska

Species-specific differences In the recipient cell’s cytoplasmic environment of in the reprogramming status of donor the majority of mammalian species embryos, exclud- nuclear DNA epigenomic inheritance ing sheep, heavily methylated somatic cell-inherited between mammalian somatic cell cloned genome has to undergo wide epigenetic changes, embryos which allow to erase its own methylation pattern es- tablished during cell differentiation and to restore nu- Transcriptional activity (gene expression or re- clear totipotency/pluripotency during early em- pression) of the somatic cell genome during pre- and bryogenesis. The studies aimed at examining develop- postimplantation development of cloned embryos de- ment of murine preimplantation embryos (Kishigami pends generally on the reprogramming extent of epi- et al. 2006, Esteves et al. 2011, Mason et al. 2012) genetic modifications such as demethylation/methyla- have shown not only differential (asymmetric) de- tion of nuclear DNA cytosine residues as well as methylation waves of nucleosomal histones of acetylation/deacetylation and demethylation/methyla- topologically-separated parental genomes that had tion of lysine moieties within chromatin nucleosomal been previously configured into female and male core-derived histones H3 and H4. It has been ascer- pronuclei in the fertilized eggs, but also genome-wide tained that the donor genomic DNA should undergo DNA methylation changes during preimplantation both the global and developmentally-important development. It cannot also be excluded that zygotic gene-selective demethylation processes throughout demethylation and genome-wide methylation changes the early embryogenesis of nuclear transfer-derived are not a prerequisite for normal development of oocytes to reset its own epigenetic memory estab- ovine embryos, in which a global DNA demethylation lished as a result of specific differentiation pathway of wave does not occur immediately after fertilization of somatic and germ cell lineages (Martinez-Diaz et al. ova. Despite incomplete and delayed demethylation 2010, Buganim et al. 2013, Masala et al. 2017). processes within somatic genome that had been trans- Against a background of other mammalian species ferred into the artificially activated eggs, some mam- zygotes that undergo active male pronuclear de- malian cloned embryos developed apparently nor- methylation wave, in rabbits, both the paternally- and mally (Rodriguez-Osorio et al. 2012, Anckaert and maternally-inherited genomes appear to maintain the Fair 2015, Huang et al. 2016). relatively high DNA methylation level during preimplantation development up to the 16-cell stage. Ad- mittedly, the correlation between the frequency of nu- Influence of oocyte reconstruction technique clear DNA demethylation and advanced degree of (somatic cell nuclear transfer/SCNT method) chromatin architectural remodelling has been sugges- on the fate of the processes for architectural ted (Shi et al. 2004, Yang et al. 2007, Nashun et al. remodeling and epigenetic reprogramming 2015). Nevertheless, this dependence is presumably of donor genome in cloned embryos insufficient, because the sperm-derived genome (male pronucleus) in non-mammalian species undergoes the Nucleoplasmic (karyolymphatic) factors of a so- spatial rearrangements of chromatin nucleosomal matic cell that are engaged directly or indirectly in its conformation without active demethylation of DNA structural and functional differentiation are asso- cytosine residues. Although active (replication-inde- ciated with nuclear chromatin and their qualitative pendent) demethylation of nuclear genome seems to and quantitative composition undergoes changes to- be preserved by the embryos of different mammalian gether with progressing cytodifferentiation state species, in the rabbit embryos high DNA methylation (Campbell and Alberio 2003, Eilertsen et al. 2007, levels were found to be maintained during preimplan- Fisher and Fisher 2011). The previously-mentioned tation development (Shi et al. 2004, Corry et al. 2009, nucleoplasmic factors involve among others transcrip- Shi and Wu 2009). In contrast, Lepikhov et al. (2008) tion factors, histones, non-histone HMG (high mobil- have shown that, in rabbit nuclear-transferred em- ity group) proteins interacting with transcription- bryos at the 1-cell stage, the fibroblast cell-inherited ally-active chromatin, nuclear lamins and poly-subunit genomic DNA undergoes rapid demethylation im- protein complexes that are responsible for remodeling mediately after activation of reconstituted oocyte of spatial conformation of chromatin structures and (clonal cybrid) and formation of pseudopronucleus. for DNA topology changes. These latter include, e.g., Nonetheless, in ovine embryos derived from fertilized nucleosome remodeling factor (NURF), brahma fam- ova, a dramatic decrease in genomic DNA methyla- ily proteins (BRG1 and BRM) sharing homology with tion status was not found until the 16-blastomere related yeast factors SWI2/SNF2 (switch of mating stage will not have been reached by them (Beaujean type/sucrose non-fermenting) and multimeric epi- et al. 2004, Wen et al. 2014, Jafarpour et al. 2017). genetic modifiers, the members of which are: tran- Intrinsic and extrinsic molecular determinants... 219 scriptional activator complexes such as Trithorax dleder 2007). Moreover, reducing the volume of al- group (Trx-G) proteins and transcriptional repressor logeneic somatic cell-derived cytoplasm, which is complexes such as Polycomb group (Pc-G) proteins transplanted into the cytosolic microenvironment of (Andreu-Vieyra and Matzuk 2007, Rajasekhar and ooplast, allows to completely prevent the limitations Begemann 2007, Whitworth and Prather 2010, caused by the hybridization of heteroplasmic sources Buganim et al. 2013). When G0/G1-stage or of not only mitochondrial DNA (mtDNA) copies G2/M-stage whole donor cell is fused with enucleated (Fig. 1), but also cytoplasmic and intramitochondrial oocyte by electroporation or microinjected directly translation system-descended messenger RNAs (in- into the ooplast cytoplasm, then those specific factors cluding also polycistronic mitochondrial mRNA frac- of a somatic cell are also transferred into the cytop- tions), transporter RNAs as well as ribosomal RNAs. lasm of recipient oocyte and may block an ability of All these mtDNA or RNA fractions of heteroplasmic endogenous oocyte factors for appropriate remodel- origin are inherited both from nuclear donor somatic ing/reprogramming of both epigenetic and genomic cell and from nuclear recipient cytoplast (ooplast) imprinting memory in foreign (allogenic) cell nucleus (Roh and Hwang 2002, Bowles et al. 2007, Jin et al. (Armstrong et al. 2006). Exogenous cytoplasmic fac- 2017a). The lack of the impurities in the form of so- tors of donor cell are incorporated together with own matic cell-inherited mtDNAs in the cytoplasmic envi- proteins and maternal transcripts (mRNA molecules) ronment of reconstructed oocyte, or the lack of the of oocyte into the remodeled somatic cell nucleus so-called mtDNA heteroplasmy (Fig. 1) brings about (pseudopronucleus), after its formation in a conse- a consequent decrease in the frequency of the dis- quence of activating reconstructed (SCNT-derived) orders in the epigenetic reprogramming of nuclear oocyte (Prather et al. 2009, Narbonne et al. 2012, DNA and mtDNA (due to hypermethylation or ex- Ho¨rmanseder et al. 2017). In turn, an overabundance cessive demethylation of DNA cytosine residues) of these hypothetical foreign agents in the ooplasm (Burgstaller et al. 2007, Whitworth and Prather 2010, causes a considerable dilution of specific internal Mallol et al. 2014, 2016). For those reasons, all the oocyte factors (due to bilateral resuspending/mixing in disturbances in dynamic homeostasis of epigenetic the hybrid cytoplasmic environment), diminishing modifications of somatic cell genome may result from simultaneously the probability of complete donor nu- asynchronous structural remodeling of nuclear cleus reprogramming (Reik 2007, Van Thuan et al. chromatin and thereby non-coordinated deacetyla- 2009, Yan et al. 2010). On the contrary, the chief pur- tion/acetylation of histones and elevation of nuc- pose of intraooplasmic microinjection of leosomal repression level through decrease of G0/G1-phase karyoplast-mediated somatic cell nu- SWI2/SNF2 protein complex activity (Kumar et al. cleus is to avoid all the above-mentioned problems 2007, 2013, Liang et al. 2015, Jin et al. 2017b). They related to the biochemical/molecular processes that may also be triggered by asynchronous changes of spa- occur in the nuclear-cytoplasmic hybrid (cybrid)-de- tial configuration of regulatory segments in the scended cells of preimplantation cloned embryos im- so-called displacement loop (D-loop) of` naked’ circu- mediately after electrically-induced fusion of G0/G1- lar mtDNA molecules within the blastomeres of nu- or G2/M-stage somatic cell-ooplast couplets. These clear-transferred embryos (Hiendleder 2007, Zhao et problems at the molecular level can also take place in al. 2010a, Srirattana et al. 2011, Narbonne et al. 2012). mammalian cloned embryos generated by direct The maintenance of correct DNA methylation pattern microinjection of quiescent or cycling whole cells into in the cell nuclei of all descendant blastomeres of the cytoplasm of enucleated oocytes (Roh and Hwang preimplantation cloned embryos favors also the pres- 2002, Kawano et al. 2004, Esteves et al. 2011). Intro- ervation in the intact form of the mechanisms respon- duction of practically only the donor cell nucleus at sible for parental genome imprinting, i.e., uniparental/ the G0/G1 or G2/M phases of mitotic cycle into the /monoallelic gene expression. In turn, this is reflec- cytoplasm of enucleated oocyte increases many times ted in proper rearrangement of exogenous chromatin the probability of proper action of specific cytosolic as well as faithful reprogramming of nuclear and oocyte agents on the processes of foreign nuclear mitochondrial (cytoplasmic) genetic apparatuses in- chromatin remodeling and genome reprogramming, herited from the somatic cell. But, in the extreme because in this case the only source of exogenous pro- cases, this is even accompanied by partial remodeling teins and mRNA transcripts is the nucleoplasm of of nuclear donor cell-derived chromatin structures, transplanted karyoplast. Insignificant numbers of which enables avoiding the inhibition of transcrip- perinuclear cytoplasm (perikaryon) remain presum- tional activity of a larger part of embryonic genome ably without a greater effect on the further embryonic in the early stages of cloned embryo development development of mammalian clonal zygotes (Galli et (Yan et al. 2011, Saini et al. 2014, Nashun et al. al. 2002, Kurome et al. 2003, Lee et al. 2003, Hien- 2015). 220 M. Samiec, M. Skrzyszowska

Fig. 1. Distribution of donor cell-inherited mtDNAs in nuclear-transferred oocytes reconstructed by intracytoplasmic microinjection of somatic cell-derived karyoplasts. By using the pipette, whose sharp bevelled tip has an external diameter about half the size of the selected cell, the plasma membrane is broken by gentle repeated aspiration of the entire cell into and out of the pipette. Thus, the cell nucleus with residual, perinuclear protoplasmic “ring” (i.e., perikaryon) is isolated. This live-membrane structure that has been obtained by mechanically induced lysis of the somatic cell is designated as a karyoplast. The karyoplast can also contain low numbers of somatic cell-derived mitochondria within the perikaryon. Therefore, the proportion of nuclear donor mtDNA copies in the clonal cytoplasmic hybrids (cybrids) seems to be related to the quantity of somatic cell cytoplasm present post reconstruction of enucleated oocytes.

Endogenous and exogenous factors lasmic, nuclear and epigenomic maturity of enuc- responsible for architectural remodeling leated host oocyte (ooplast/cytoplast) for somatic and epigenetic remodeling/reprogramming cell-inherited nuclear genome, involve many pathways of somatic cell-inherited chromatin in of intracellular enzymatic machinery. The most im- a cytoplasm of nuclear-transferred oocytes portant protein members of this machinery are cyclin-dependent kinases (CDKs). At the metaphase II The establishment of epigenomic maturity (MII) stage of the meiotic cell cycle, they include, in nuclear recipient oocytes among others, maturation/meiosis-promoting factor (MPF) and cascade of mitogen-activated protein The remodeling and reprogramming of somatic kinases (C-MAPKs) related to the activity of cytos- cell-derived nuclear apparatus in cloned embryos is tatic factor (CSF). MPF is a heterodimeric enzyme a result of interaction of protein factors accumulated complex that consists of the catalytic subunit cdc2 in the nucleoplasm and attached to the chromatin, (p34 /CDK1; 34-kDa cell division control protein configured in the form of metaphase plate in conse- kinase 2/cyclin-dependent protein kinase 1) and the quence of appropriate rearrangement of its spatial regulatory subunit (cyclin B). Furthermore, at the structure and nucleosome repression, with protein anaphase II (AII) stage, the protein factors regulating factors of recipient oocyte cytoplasm (i.e., host oop- the oocyte meiotic division cycle include, e.g., lasm). Both former and latter protein factors, whose poly-subunit protein complex of ubiquitin ligase that concentration and activity at the high levels are the was named anaphase-promoting complex or cyclo- prerequisites for establishment of the state of cytop- some (APC/C) (Lee and Campbell 2006, Prather et al. Intrinsic and extrinsic molecular determinants... 221

2009). Aside from determination of cytoplasmic and both the timing and rate of the cytoplasmic and epi- nuclear (meiotic) maturity of recipient oocytes, the genomic maturation as well as the degree and rapidity above-mentioned CDKs bias the architectural re- of synchronization between cytoplasmic, epigenomic modeling of oocyte-descended microtubule organiz- and nuclear (meiotic) maturation can be affected by ing centers (MTOCs) or, more precisely, its acentrio- the treatment of immature (GV-stage) oocytes with lar meiotic spindle poles (astrospheres). Additionally, the above-mentioned agents. Moreover, the develop- they impact the spatial remodeling of both nuclear mental competences of somatic cell cloned embryos donor somatic cell-inherited chromatin and MTOCs derived from nuclear recipient oocytes that have been (i.e., dicentriolar centrosomes or tetracentriolar diplo- matured in vitro in such conditions can also be in- somes) that have been transplanted into host ooplasm fluenced, to a high degree, by the modulators of (Fissore et al. 1999, Campbell and Alberio 2003, Ito et cytoplasmic and epigenomic ex vivo maturation (Coy al. 2004). In turn, the presence of intrinsic epigenetic et al. 2005, Schoevers et al. 2005, Kishigami et al. determinants and/or modifiers has been found to be 2006, Bui et al. 2007, Samiec and Skrzyszowska 2012, indispensable both for attaining epigenomic maturity Liang et al. 2015, Xie et al. 2016). by MII-stage oocytes and for acquiring epigenomic competence by nuclear-transferred (NT) oocytes that have been artificially activated to induce their release Epigenomic modulation (epigenetic from MII arrest and meiosis resumption. The crucial transformation) of nuclear donor somatic representatives of these endogenous epigenetic fac- cells, nuclear recipient oocytes and/or in vitro tors and modulatory proteins are: 1) competitive in- cultured cloned embryos – its influence hibitors of DNA methyltransferases/methylases (in- on both remodeling of somatic cell-derived hibitors of DNMTs; iDNMTs) such as isosteric chromatin and reprogramming blockers of the DNMT1o and DNMT3a/3b isoen- of transcriptional activity of somatic zymes; 2) repressors of activity of methyl-CpG-bind- cell genome ing proteins (MeCPs; proteins binding methylated 5’-cytidine-3’-monophosphate-5’-guanosine-3’/CpG Transcriptional activity of somatic cell-inherited dinucleotides/motifs); and 3) histone H3 and H4 nuclear genome during embryo pre- and/or postim- acetyltransferases/acetylases (HATs) (Beaujean et al. plantation development as well as foetogenesis is cor- 2004, Bonk et al. 2008, Das et al. 2010, Rod- related with the frequencies for spatial remodeling of riguez-Osorio et al. 2012, Masala et al. 2017). The chromatin architecture and reprogramming of cellular other pivotal intrinsic epigenetic modulators, which epigenetic memory. These former and latter processes are accumulated in the cytoplasm and nucleoplasm of include such covalent modifications as demethyla- NT oocytes stimulated to initiate embryonic develop- tion/de novo methylation of DNA cytosine residues ment, encompass: 4) isosteric inhibitors of histone and acetylation/deacetylation as well as demethyla- deacetylases (HDACs); 5) supressory proteins of hi- tion/re-methylation of lysine residues of nucleosomal stone methyltransferases (HMTs); 6) histone de- core-derived histones H3 and H4 (Wee et al. 2007, methylases/deiminases (HDMs); as well as 7) Ding et al. 2008, Lee et al. 2010, Song et al. 2014, multi-subunit protein complexes with the activity of Liang et al. 2015, Jin et al. 2017a). In addition, inter- ATPases such as chromatin remodeling complexes genomic communication between heteroplasmically (ChRs) (Yamanaka et al. 2009, Zhao et al. 2009, transmitted nuclear DNA, maternally (ooplasmically) 2010a, Whitworth and Prather 2010, Nashun et al. inherited copies of mitochondrial DNA (mtDNA) 2015, Anckaert and Fair 2015, Ho¨rmanseder et al. and nuclear donor cell-descended copies of mtDNA 2017). affects the profile of gene expression. It also affects The use of ectopic repressory proteins for selec- the nuclear-ooplasmic interactions in cloned embryos tive/specific or non-selective/non-specific CDK inhibi- and foetuses (Shi et al. 2004, Yan et al. 2010, 2011). tion (e.g., R-roscovitine, butyrolactone I or The level of progression for the processes of epi- 6-dimethylaminopurine) and/or exogenous epigenetic genetic genome-wide alterations that are mediated by modifiers (e.g., non-specific inhibitors of DNMTs or histone-lysine methyltransferases (HMTs), DNA inhibitors of HDACs) throughout in vitro maturation methyltransferases (DNMTs 1o and 3a/3b) and hi- of mammalian dictyotene- or germinal vesicle stone deacetylases (HDACs) can be modulated (i.e., (GV)-stage oocytes can affect, on the one hand, the reversed) via exogenous inhibitors of these enzymes ability of the oocytes that reached MII stage to attain throughout either in vitro culture of nuclear donor the cytoplasmic and epigenomic maturity states (i.e., somatic cells and/or cloned embryos (Martinez-Diaz before or simultaneously with acquisition of the nu- et al. 2010, Bo et al. 2011, Ning et al. 2013, Sangalli et clear/meiotic maturity by them). On the other hand, al. 2014, Huang et al. 2016) or in vitro maturation of 222 M. Samiec, M. Skrzyszowska nuclear recipient oocytes (Samiec and Skrzyszowska termed PCI-24781 [3-[(dimethylamino)methyl]- 2012, Samiec et al. 2016). Moreover, the use of the N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-ben- artificial modifiers of epigenomically-conditioned zofuran-2-carboxamide] (Jin et al. 2016); 9) quisinos- gene expression, leads to the inhibition of both tat, also called JNJ-26481585 [N-hydroxy-2- chromatin condensation and transcriptional silencing [4-[[[(1-methyl-1H-indol-3-yl)methyl]amino]methyl]-1 the genomic DNA of cultured somatic cells that are -piperidinyl]-5-pyrimidinecarboxamide] (Jin et al. applied as a source of donor nuclei for the reconstruc- 2017a); 10) dacinostat, also named as LAQ824 or tion of enucleated oocytes and subsequent generation NVP-LAQ824 [(E)-N-hydroxy-3-[4-[[2-hydroxyethyl- of cloned embryos (Zhao et al. 2010b, Su et al. 2011, [2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2- Wang et al. 2011a,b). On the one hand, those epi- enamide] (Jin et al. 2017b); 11) belinostat, also known genetic modifiers represent not only the subclass of as PXD101 [(E)-N-hydroxy-3-[3-(phenylsulfamoyl) highly specific/selective extrinsic HMT inhibitors phenyl]prop-2-enamide or N-hydroxy-3-[3-(phenylsul- (HMTi) such as G9A (H3K9) HMTi, the pivotal famoyl) phenyl]-2-propenamide] (Qiu et al. 2017); member of which is diazepin-quinazolin-amine de- and 12) bromotyrosine-derived, symmetrical conju- rivative termed BIX-01294 [2-(hexahydro-4-methyl- gate of cystamine (antibiotic first isolated from the 1H-1,4-diazepin-1-yl)-6,7-dimethoxy-N-[1-(phenyl- Psammaplinaplysilla marine sponge and probably ex- methyl)-4-piperidinyl]-4-quinazolinamine or hibiting also the DNMTi and anti-tumor activity), des- N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl ignated as psammaplin A or bisprasin, (PsA; -1,4-diazepan-1-yl)quinazolin-4-amine] (Huang et al. N,N’’-(dithiodi-2,1-ethanediyl)bis[3-bromo-4-hydroxy- 2016, Cao et al. 2017), but also the subclass of ectopic a-(hydroxyimino)-benzenepropanamide or (2E)-3- non-specific DNMT inhibitors (DNMTi), whose the (3-bromo-4-hydroxyphenyl)-N-[2-[2-[[(2E)-3-(3-bro- most important members are: 1) 5-aza-2’- mo-4-hydroxyphenyl)-2-hydroxyiminopropanoyl]amin -deoxycytidine (5-aza-dC; decitabine) (Enright et al. o]ethyldisulfanyl]ethyl]-2-hydroxyiminopropanamide) 2005, Ding et al. 2008, Ning et al. 2013, Huan et al. (Mallol et al. 2014, 2015, 2016). The onset of 2013, 2014, 2015a,b); 2) zebularine (2-pyrimidone-1- chromatin decondensation and gene transcriptional -β-D-riboside; a nucleoside analog of cytidine) (Diao activity is evoked both via highly specific/selective and et al. 2013, Xiong et al. 2013); and 3) S-adenosyl- transient inactivation of G9A (H3K9) HMTs by homocysteine (SAH) (Jeon et al. 2008). On the other BIX-01294 (Huang et al. 2016, Cao et al. 2017) and hand, they represent the subclass of ectopic non-selec- via non-specific/non-selective (i.e., broad-spectrum) tive HDAC inhibitors (HDACi), whose main mem- blocking the biocatalytic activity of either DNMTs by bers are: 1) trichostatin A (TSA; [R-(E,E)]-7-[4- 5-aza-dC, zebularine and SAH (Jeon et al. 2008, Diao -(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-o et al. 2013, Huan et al. 2015a,b) or HDACs by TSA, xo-2,4-heptadienamide) (Li et al. 2008, Cervera et al. VPA/SV, SCPT, oxamflatin, NaBu, CBHA, 2009, Bo et al. 2011, Saini et al. 2014, Huan et al. panobinostat, abexinostat, quisinostat, dacinostat, be- 2014, 2015a,b, Samiec et al. 2015, Opiela et al. 2017); linostat and PsA (Kim et al. 2011, Park et al. 2012, Jin 2) valproic acid/2-propylpentanoic acid (VPA) or so- et al. 2013, Kumar et al. 2013, Xu et al. 2013, Song et dium valproate/sodium 2-propylpentanoate (SV) al. 2014, Mallol et al. 2015, Jin et al. 2016, 2017a,b, (Costa-Borges et al. 2010, Kim et al. 2011, Mallol Qiu et al. 2017). Such exogenous epigenomic modula- et al. 2014, Sangalli et al. 2014); 3) scriptaid tion (epigenetic transformation) of nuclear donor (SCPT; 6-(1,3-dioxo-1H,3H-benzo[de]isoquinolin- cells, nuclear recipient cells and/or cloned embryos -2-yl)-hexanoic acid hydroxyamide) (Van Thuan et al. may facilitate and accelerate the reprogrammability 2009, Zhao et al. 2009, Xu et al. 2013, Wen et al. 2014, for gene expression of donor cell nuclei that have Liang et al. 2015, Samiec et al. 2016); 4) oxamflatin been transplanted into cytoplasmic microenvironment [(2E)-5-[3-(phenylsulfonylamino)phenyl]-pent-2-en-4- of recipient oocytes and subsequently undergo the de- ynohydroxamic acid or N-hydroxy-5-[3-[(phenylsul- differentiating and re-establishing the epigenetically fonyl)amino]phenyl]-2E-penten-4-ynamide or (E)- dependent status of their transcriptional activity dur- -5-[3-(benzenesulfonamido)phenyl]-N-hydroxypent-2- ing the preimplantation development of cloned em- en-4-ynamide] (Su et al. 2011, Park et al. 2012, Hou et bryos (Van Thuan et al. 2009, Martinez-Diaz et al. al. 2014, Mao et al. 2015); 5) sodium butyrate (NaBu) 2010, Bo et al. 2011, Huan et al. 2015a,b, Huang et al. (Das et al. 2010, Liu et al. 2012, Kumar et al. 2013); 6) 2016, Jin et al. 2017b). The indirect exogenous m-carboxycinnamic acid bishydroxamide (CBHA) DNMTi- and/or direct ectopic HDACi-induced hy- (Dai et al. 2010, Song et al. 2014); 7) panobinostat, peracetylation of lysine residues on nucleosomal also known as LBH589 [(E)-N-hydroxy-3-[4-[[2-(2- core-related histones H3 and H4 can play a role of -methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]pro epigenetic recognition coding system for the increased p-2-enamide] (Jin et al. 2013); 8) abexinostat, also recruitment of histone acetyltransferases (HATs) and Intrinsic and extrinsic molecular determinants... 223 the enhanced association of double bromodomain- inhibitors of these enzymes throughout in vitro culture -containing chromatin adaptor protein-4 (BRD4) of nuclear donor cells, nuclear recipient oocytes molecules to acetylated histones of meiotic condensed and/or cloned embryos (Su et al. 2011, Wang et al. chromosomes in the in vitro-maturing oocytes. It has 2011a, Mason et al. 2012, Gonzales-Cope et al. 2016). been shown that the preferential binding of BRD4 The use of the artificial modifiers of epigenomi- proteins to lysine moieties of hyperacetylated core hi- cally-conditioned gene expression leads to inhibition stones forming the octomeric nucleosome contributes of both chromatin condensation and transcriptional to the rhythmic conversion of transcriptionally repres- silencing the genomic DNA of somatic cells that pro- sive chromatin (heterochromatin) to the transcrip- vide a source of nuclear donors for reconstruction of tionally permissive chromatin (euchromatin) enucleated oocytes and generation of cloned embryos (Rybouchkin et al. 2006, Nagashima et al. 2007, Wang (Martinez-Diaz et al. 2010, Fisher and Fisher 2011, et al. 2011b, Liang et al. 2015, Gonzales-Cope et al. Song et al. 2014). The onset of chromatin deconden- 2016, Cao et al. 2017). As a result, after replacement sation and gene transcriptional activity is evoked via of metaphase II chromosomes in the oocytes with the highly specific blocking the activity of HMTs by somatic cell-inherited chromatin, extrinsic (e.g., TSA- BIX-01294 (Huang et al. 2016) and via broad-spec- or SCPT-mediated) inhibition of global histone trum blocking the activity of either DNMTs by deacetylation through down-regulation of HDAC ac- 5-aza-2’-deoxycytidine, zebularine, S-adenosyl- tivity can facilitate and accelerate the architectural re- homocysteine (Jeon et al. 2008, Huan et al. 2013, modeling and epigenetic reprogramming processes of Xiong et al. 2013) or HDACs by trichostatin A, val- nuclear donor cell-descended chromatin within the proic acid/sodium valproate, scriptaid, oxamflatin, so- preimplantation cloned embryos. It is, therefore, con- dium butyrate, m-carboxycinnamic acid bishydroxam- ceivable that the erasing of epigenomic memory can ide, panobinostat, abexinostat, quisinostat, dacinostat, occur in the somatic cell nuclei after their introduc- belinostat and psammaplin A (Dai et al. 2010, Bo et tion into the cytoplasm of enucleated oocytes (Das et al. 2011, Kim et al. 2011, Wang et al. 2011b, Jin et al. al. 2010, Zhao et al. 2010b, Samiec et al. 2016, Opiela 2013, Ning et al. 2013, Mallol et al. 2014, Mao et al. et al. 2017, Qiu et al. 2017). This can thereby give rise 2015, Samiec et al. 2015, Jin et al. 2016, 2017a,b, Qiu to the remarkable transformation of cytosine residue et al. 2017). Epigenomic modulation of nuclear donor methylation marking of nuclear donor DNA from epi- cells, nuclear recipient cells and/or cloned embryos genetic pattern of differentiated cells into the may facilitate and accelerate the reprogrammability totipotent dedifferentiated status of embryonic (i.e., for gene expression of donor cell nuclei that have zygotic) cells. Furthermore, the establishment of been transplanted into a host ooplasm and subse- a transcriptionally permissive chromatin state within quently underwent dedifferentiating and re-establish- the rearranged donor cell nuclei via inducible active ing the epigenetically dependent status of their tran- acetylation of histones H3 and H4 followed by in- scriptional activity during pre- and postimplantation direct genome-wide demethylation of DNA cytosine development of NT embryos (Eilertsen et al. 2007, Shi residues can cause the silencing of gene expression to and Wu 2009, Costa-Borges et al. 2010, Samiec and cease in the cells of nuclear-transferred (NT) embryos Skrzyszowska 2012, Hou et al. 2014, Samiec et al. developing to the morula and blastocyst stages (Wee 2016, Cao et al. 2017, Opiela et al. 2017). et al. 2007, Shi and Wu 2009, Wang et al. 2011a, Diao Summing up, while tremendous progress in the et al. 2013, Hou et al. 2014, Samiec et al. 2015, Jin et field of somatic cell cloning has been achieved during al. 2016, 2017a). the past few years with the birth of numerous off- spring of different mammalian species worldwide, the overall efficiency remains low. The current high inci- Conclusions and future goals dence of pre- and/or postimplantation embryonic, foe- tal as well as perinatal abnormalities limits the practi- Incomplete and aberrant reprogramming of epi- cal applications of somatic cell cloning and contrib- genetic memory of somatic cell nuclei in preimplanted utes to the negative perception of this assisted repro- nuclear-transferred (NT) embryos is one of the most ductive technology (ART) to society. The aims are to important factors that limit the cloning effectiveness understand the mechanisms involved in the aberra- (Bonk et al. 2008, Buganim et al. 2013, Nashun et al. tions for both wide epigenetic transcriptional reprog- 2015). The extent of epigenetic genome-wide alter- ramming of donor cell-descended nuclear DNA and ations involving DNA methylation and histone differential (maternal or paternal) expression patterns deacetylation that are mediated by DNA methyltran- of several imprinted (i.e., uniparentally-expressed) sferases (DNMTs) and histone deacetylases genes that can lead to the pathologic syndromes in (HDACs) can be modulated/reversed via exogenous cloned foetuses and neonates (Zhao et al. 2010a, Des- 224 M. Samiec, M. Skrzyszowska hmukh et al. 2011, Esteves et al. 2011, Anckaert and Buganim Y, Faddah DA, Jaenisch R (2013) Mechanisms Fair 2015, Jafarpour et al. 2017, Masala et al. 2017). and models of somatic cell reprogramming. Nat Rev Genet 14: 427-439. Burgstaller JP, Schinogl P, Dinnyes A, Muller M, Steinborn R(2007) Mitochondrial DNA heteroplasmy in ovine fe- Acknowledgments tuses and sheep cloned by somatic cell nuclear transfer. BMC Dev Biol 7: 141. 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